This invention relates to methods for reducing the incidence of sudden death in certain patients by administering thereto a pharmaceutically effective amount of a corticotropin releasing factor (CRF) antagonist. It is currently believed that CRF antagonists reduce the incidence of sudden death in patients by improving their QT dispersion and heart rate variability.
Sudden unexpected death occurs in about 50% of patients suffering from mild heart failure and in 25% of patients experiencing severe heart failure (Barr et al., Lancet, 343(8893):327-29 (1994)). Regional variation in ventricular repolarization, which represents an electrophysiological substrate for arrhythmias, can be detected by inter-lead variability of the QT interval (dispersion). Increased QT interval dispersion has been shown in patients who develop ventricular tachyarrhythmias after an acute myocardial infarction, long QT syndrome, chronic heart failure, and hypertrophic cardiomyopathy (see, e.g., Potratz et al., Eur. Heart J., 14:254 (1993); Day et al., Br. Heart J., 63:342-44 (1990); and Buja et al., Am. J. Cardiol., 72:973-976 (1993)).
The compounds of formulas I and II as described herein, their pharmaceutically acceptable salts, and methods of preparing such compounds and salts are disclosed in European patent application number EP 0773023 A1, and in more detail in PCT international patent application numbers PCT/IB95/00373 (published as WO 95/34563), PCT/IB95/00439 (published as WO 95/33750), PCT/US93/11333 (published as WO 94/13677), and PCT/US93/10715 (published as WO 94/13676). These European and PCT international patent applications, referred to above, are incorporated herein by reference in their entirety.
The foregoing PCT international patent applications refer to the use of the compounds of formulas I and II in the treatment of illnesses induced or facilitated by CRF and in the treatment of anxiety, depression, fatigue syndrome, gastrointestinal diseases, headache, pain, cancer, immune dysfunction, hemorrhagic stress, drug addiction, drug and alcohol withdrawal symptoms, fertility problems, stress-induced psychotic episodes, neurodegenerative diseases such as Alzheimer""s disease, irritable bowel syndrome including Crohn""s disease, spastic colon, and irritable colon, eating disorders such as anorexia nervosa, inflammatory disorders such as arthritis, asthma, and allergies.
Other CRF antagonists that can be used to treat the disorders recited in the method of this invention are referred to in PCT international patent application numbers PCT/IB95/00318 (published as WO 95/33727), PCT/IB97/00918 (published as WO 98/05661), PCT/IB97/00904 (published as WO 98/08846), and PCT/IB97/00922 (published as WO 98/08847), PCT/EP98/02267 (published as WO 98/47874), PCT/EP98/02268 (published as WO 98/47903), PCT/US98/09861 (published as WO 98/51312), PCT/US98/13840 (published as WO 99/01439), PCT/US98/13913 (published as WO 99/01454), as well as in U.S. Pat. Nos. 5,063,245, 5,109,111, 5,132,111, 5,245,009, 5,464,847, 5,493,006, 5,510,458, 5,605,642, 5,644,057, 5,663,292, 5,668,145, 5,705,646, and 5,712,303. All of the above-cited PCT international patent applications and United States Patents are incorporated herein by reference in their entirety.
The importance of CRF antagonists is set out in the literature, e.g., as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference in its entirety. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., 43:425-73 (1991), also incorporated herein by reference in its entirety.
PCT international patent application PCT/US98/07831 (published as WO 98/47899) discloses the usefulness of substituted pyrrolopyridines in the treatment of inflammatory diseases. The disclosed compounds inhibit the production of certain inflammatory cytokines, namely TNF-xcex1 and IL-1xcex2. One of the listed cytokine-related inflammatory diseases is congestive heart failure. However, no mention is made of QT dispersion or heart rate variability.
The present invention relates to a method of preventing sudden death in an animal comprising administering to said animal, preferably a human, a therapeutically effective amount of a corticotropin releasing factor antagonist.
The method of the present invention is most useful in preventing sudden death in specific patients, particularly those suffering from cardiovascular or heart related diseases such as hypertension, tachycardia, congestive heart failure, and the like, as well as other diseases such as stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, colonic hypersensitivity associated with psychopathological disturbance and stress, and the like. The method of the present invention is also useful in preventing sudden death in diabetic patients, as well as in patients suffering from many neurological disorders such as brain damage, Guillain-Barre syndrome, sudden infant death syndrome, congenital hypoventilation syndrome, uremic neuropathy, and the like.
In a preferred embodiment, the present invention is practiced using a compound of Formula I or II: 
or a pharmaceutically acceptable salt thereof, wherein
the dashed line represents an optional double bond;
A is xe2x80x94CR7 or N;
B is xe2x80x94NR1R2, xe2x80x94CR1R2R11, xe2x80x94C(xe2x95x90CR1R12)R2, xe2x80x94NHCR11R1R2, xe2x80x94OCR11R1R2, xe2x80x94SCR11R1R2, xe2x80x94CR11R2OR1, xe2x80x94CR11R2SR1, xe2x80x94C(S)R2, xe2x80x94NHNR1R2, xe2x80x94CR2R11NHR1 or xe2x80x94C(O)R2;
D is
N or xe2x80x94CR10 when a double bond connects E and D and E is xe2x80x94CR4;
xe2x80x94CR10 when a double bond connects E and D and E is N; or
xe2x80x94CR8R9, xe2x80x94CHR10, xe2x80x94Cxe2x95x90O, xe2x80x94Cxe2x95x90S, xe2x80x94Cxe2x95x90NH, or xe2x80x94Cxe2x95x90NCH3 when a single bond connects E and D;
E is xe2x80x94CR4 or N when a double bond connects E and D, and E is xe2x80x94CR4R6 or xe2x80x94NR6 when a single bond connects E and D;
Y is N or xe2x80x94CH;
Z is NH, O, S, xe2x80x94N(C1-C2 alkyl), or xe2x80x94CR12R13, wherein R12 and R13 are each, independently, hydrogen, trifluoromethyl, or methyl, or one of R12 and R13 is cyano and the other is hydrogen or methyl;
R1 is hydrogen or C1-C6 alkyl which is optionally substituted with up to two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF3, C1-C4 alkoxy, xe2x80x94Oxe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94NH(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94N(C1-C4alkyl)CO(C1-C4 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, and (C1-C4 alkyl)sulfanyl, and wherein said C1-C6 alkyl, C1-C4 alkoxy, and C1-C4 alkyl moieties in the foregoing R1 groups optionally contain one double or triple bond;
R2 is C1-C6 alkyl, heteroaryl, aryl, heteroaryl (C1-C4 alkyl), or aryl (C1-C4 alkyl), wherein said aryl and the aryl moiety of said (aryl)C1-C4 alkyl are selected from the group consisting of phenyl and naphthyl, and said heteroaryl and the heteroaryl moiety of said (heteroaryl)C1-C4 alkyl is selected from the group consisting of thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R2 is C3-C8 cycloalkyl or (C3-C8 cycloalkyl)C1-C6 alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C3-C8 cycloalkyl)C1-C6 alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by -NR14 wherein R14 is hydrogen or C1-C4 alkyl; and wherein each of the foregoing R2 groups is optionally substituted by up to three substituents independently selected from chloro, fluoro, and C1-C4 alkyl, or by one substituent selected from bromo, iodo, cyano, nitro, C1-C6 alkoxy, xe2x80x94Oxe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CO2(C1-C4 alkyl), (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfinyl, and (C1-C4 alkyl)sulfonyl, and wherein said C1-C4 alkyl and C1-C6 alkyl moieties of the foregoing R2 groups optionally contain one carbon-carbon double or triple bond;
or R1 and R2 of said xe2x80x94NR1R2 and said xe2x80x94CR1R2R11 are taken together to form a saturated or partially saturated 5- to 8-membered ring, wherein said ring optionally contains one or two carbon-carbon double bonds, and wherein one or two of the ring carbons is optionally replaced by a heteroatom selected from O, S, and N;
R3 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CH2OH, xe2x80x94CH2OCH3, xe2x80x94O(C1-C4 alkyl), (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfonyl, or (C1-C4 alkyl)sulfinyl, wherein said C1-C6 alkyl and C1-C4 alkyl moieties of the foregoing R3 groups optionally contain one double or triple bond and are optionally substituted by from one to three substituents independently selected from hydroxy, amino, C1-C3 alkoxy, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)2, xe2x80x94NHCOCH3, fluoro, chloro, and C1-C3 thioalkyl;
R4 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, formyl, trifluoromethoxy, xe2x80x94CH2OCH3, xe2x80x94CH2OCH2CH3, xe2x80x94CH2CH2OCH3, xe2x80x94CH2CF3, CF3, amino, nitro, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(CH3)2, xe2x80x94NHCOCH3, xe2x80x94NHCONHCH3, (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, cyano, hydroxy, xe2x80x94CO(C1-C4 alkyl), xe2x80x94CHO, or xe2x80x94CO2(C1-C4 alkyl), wherein said C1-C6 alkyl, C1-C6 alkoxy, and C1-C4 alkyl moieties of the foregoing R4 groups optionally contain one double or triple bond and are optionally substituted with one substituent selected from hydroxy, amino, xe2x80x94NHCOCH3, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)2, xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CO(C1-C4 alkyl), C1-C3 alkoxy, (C1-C3 alkyl)sulfanyl, fluoro, chloro, cyano, and nitro;
R5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or a 3- to 8-membered cycloalkyl ring or a 9- to 12-membered bicycloalkyl ring system, wherein said cycloalkyl ring and said bicycloalkyl ring system optionally contain one or two of O, S, or xe2x80x94Nxe2x80x94G wherein G is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl, or benzyl, wherein each of the above R5 groups is optionally substituted by up to three substituents independently selected from fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, and trifluoromethyl, or one substituent selected from bromo, iodo, cyano, nitro, amino, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CO(C1-C4 alkyl), xe2x80x94SO2NH(C1-C4 alkyl), xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94SO2NH2, xe2x80x94NHSO2(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), and xe2x80x94SO2(C1-C4 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl moieties of the foregoing R5 groups optionally contain one double or triple bond and are optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, amino, methylamino, dimethylamino, and acetyl;
R6 is hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted by a single hydroxy, methoxy, ethoxy, or fluoro group;
R7 is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, C1-C4 alkoxy, xe2x80x94CO(C1-C4 alkyl), xe2x80x94CO2(C1-C4 alkyl), xe2x80x94OCF3, CF3, xe2x80x94CH2OH, xe2x80x94CH2OCH3, or xe2x80x94CH2OCH2CH3;
R8 and R9 are each, independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy;
or R8 and R9 together form an oxo (xe2x95x90O) group;
R10 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, formyl, amino, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), cyano, carboxy, amido, or xe2x80x94SOn(C1-C4 alkyl) wherein n is 0, 1, or 2, wherein said C1-C6 alkyl and C1-C4 alkyl moieties of the foregoing R10 groups are optionally substituted by one of hydroxy, trifluoromethyl, amino, carboxy, amido, xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CO2(C1-C4 alkyl), C1-C3 alkoxy, C1-C3 thioalkyl, fluoro, bromo, chloro, iodo, cyano, or nitro; and
R11 is hydrogen, hydroxy, fluoro, or methoxy.